Current Series: Dravet Syndrome and Lennox-Gastaut Syndrome: Recent Treatment Advances

Anup Patel, MD: Speaking of what’s out there, Ian, comment about what’s in development. You know it’s an exciting time for us. But comment on it specifically as it relates to Dravet and LGS [Lennox-Gastaut syndrome], and what’s on the horizon.

Ian Miller, MD: We spoke a little bit earlier about how much more homogenous Dravet syndrome is and the SCN1A link. Thankfully there is a burgeoning field of kinetic therapies for pediatric disease and neurological disease, in particular. So following on the effective treatments for SMA, we’re starting to think about oligonucleotides as possible therapeutic agents to treat Dravet syndrome, and potentially LGS if there’s a specific gene that’s identified in any particular patient. We’re also looking at things that affect read-through. So if there’s a stop codon there, people and investigators looking at whether you can increase expression of that gene and have it read through the stop codon.

We’re also looking at adenovector associated delivery systems. There’s a lot of different strategies for gene therapy, but ultimately it all fits under the gene therapy umbrella, which is incredibly exciting because it finally gives us an opportunity to treat the underlying cause of the epilepsy. And more importantly, part of the underlying cause of the learning and cognitive and behavioral problems, which are affected by the epilepsy, but which probably have a direct contribution from the gene mutation itself.

Anup Patel, MD: Elizabeth, anything more on the horizon that you want to mention or that you know of that’s exciting to you?

Elizabeth A. Thiele MD, PhD: No, I agree with Ian. I think we’re in a transition from just treating seizure types, and I think we need to continue to do that since we have a lot of patients with unmet need with treatment of seizures. I think it’s extremely exciting for us, for the patients, for the patient communities, that now we are beginning to think, if Dravet is an SCN1A mutation, can we target it specifically? If tuberous sclerosis is due to a mutation in one of these 2 genes, can we target that specifically? So I think that that is the beginning of an explosion of genetic therapies for many of our kids with refractory epilepsy.

Anup Patel, MD: Are there any other medications or medication trials coming that people should be aware of with Lennox-Gastaut syndrome and Dravet?

Elaine C. Wirrell, MD: There is an ongoing trial looking at TAK-935. I think those results are not out yet so we will see what that looks like. It’s a novel mechanism, but it is not sort of one that is precision that you have talked about tonight. I think that’s where the excitement really is for me is being able to target where the topogenesis is and what is actually causing the seizures plus the other developmental issues that go along with these.

Anup Patel, MD: I think it’s wonderful that these 2 syndromes have garnered such attention that has allowed for treatments to be discovered for these children in need. I think there’s still a large gap that we have to undo and obviously meet for our families and our patients, but we’re heading in the right direction.

So Eric, what advice would you give community neurologists who are treating patients with Dravet syndrome or Lennox-Gastaut syndrome?

Jesus Eric Pina-Garza, MD: Well one is that, based on the current perception, you are treating a lot of them. Be aware that they’re in your practice. For the patients who are refractory to treatment that don’t have the label, go back, and if those patients have childhood-onset epilepsy, they could have Lennox-Gastaut. If they have generalized tonic seizures, they could have Lennox-Gastaut. If you want to use the refractory epilepsy screening tool for LGS, just get it and put it in your desk and you can identify a few of them.

Our job right now, even though we don’t have every specific treatment for every specific patient, we have some treatments that work for a large percentage of the heterogeneous population, and our job is to match them. So try to remove some of the medications that can exacerbate the syndrome. Try to match them with these wide spectrum treatments that work for many. And then, again, try to provide support to this family. I think the foundations, both for Dravet and Lennox-Gastaut, do a much better job than I can do in my limited time with the family face-to-face. So for me just to connect, it makes a big difference for them.

Anup Patel, MD: Well this has been extremely informative. Before we end this discussion, I’d like to get final thoughts from each of our panelists. Ian, I’m going to start with you.

Ian Miller, MD: There were a couple of things that were said by some other panelists that I think relate to one another. Eric was talking about the idea of the diagnoses as being a movie rather than a still life. I think that was a really eloquent way to say it. And that, combined with what Elizabeth was saying here at the end, relates back to the transition a little bit from syndromes, which are obviously still incredibly important, to etiologies.

And so to me at the end of the movie, hopefully, it does have a happy ending, but I’m a little bit suspicious that the happy ending will come after the final act, which is going to be genetic diagnoses for the patients who have epilepsy. The one thing that I think is incredibly important for all neurologists is to do genetic testing as a panel so that you can identify these where they exist and give them gene appropriate therapies. Not only identify them, but also make sure that you’ve done research to see if there are gene therapies going on. Because there is an incredibly surprising amount of investigation going on and there might be an investigational trial available.

Anup Patel, MD: Elizabeth, final thoughts.

Elizabeth A. Thiele MD, PhD: I think the past 4 or 5 years have been really exciting times. It’s been great fun for us to participate in these trials and see a lot of our kids do well. I think the big take-home message for all of us though is that transition to adulthood. Because spending a lot of time talking to the advocacy groups, there really is a significant underdiagnosis of LGS and Dravet in the adult population.

And now that we have these medications that can benefit these individuals, I think it’s really important to raise awareness in the adult epilepsy neurology community that they do. As you said, they do have patients with this. And lots of times their early child history might not be available. But I think if you have an adult sitting there, if they’re still wearing a helmet or if they’re having frequent seizures, if they have intellectual disability, that patient very much likely does have LGS, may have Dravet, and could likely benefit from these new treatment modalities.

It’s not unusual for me to meet an adult with epilepsy who has not had a medication change in many years and yet is still having seizures. So I think to help make the adult neurology community aware that, hey, these people could really benefit from these medications that now are available, that can be effective and appear to be very safe and well tolerated, is an important message.

Anup Patel, MD: Elaine, how about you?

Elaine C. Wirrell, MD: Going back to what Ian has said, in adult neurology, I think become familiar with those gene panels and utilize those gene panels. I think that can be very helpful. Many of the patients in the adult side have had neuroimaging and they don’t have a lesion, but what they have not had are the gene panels, and I think that could really help with making a diagnosis.
The other thing that I’ve seen in the last 5 years is a lot of hope. These are terrible epilepsies. They have very significant impact on quality of life with the child, with the family. I think we are actually sitting in a position where hopefully shortly in the next 5, 10 years we are going to see a really increased development of precision therapies that are going to target the underlying cause of these. And each of them is going to be rare. It’s going to be incredibly important for us to collaborate. This cannot be done in one center, in one silo. We really need to collaborate to make this happen, but I think there’s a lot of good things on the horizon.

Anup Patel, MD: Eric.

Jesus Eric Pina-Garza, MD: Well I think that with both Lennox-Gastaut and Dravet, it is clearly a hard situation, hardest for the patient and the family, less for us, but hard. And clearly if you look at the diagnosis of epilepsy, we can make 60%, 70% of people seizure-free. The target is a little lower with LGS than Dravet, but it’s not zero. We have a lot of patients who return to life that has the happy ending in the movie. And we could get those happy endings more when we intervene early and aggressively. Fortunately now we have safer and better tolerated options, so we have to try them.

Anup Patel, MD: Thank you all for your contributions to this discussion. On behalf of our panel we thank you for joining us, and we hope you found this Peer Exchange discussion to be useful and informative.

In closing I would say, it’s been an honor to be your moderator for this session and be on this panel with such esteemed colleagues. And we’re very lucky to have each and every one of you helping in these diseases and treat them properly, so thank you.